RESUMO
Targeted expression of interleukin-10 (IL-10) has been proposed as a means to suppress acute and chronic inflammation. We explored the capacity of targeted adenoviral expression of human or viral IL-10 to improve outcome in a zymosan-induced model of acute lung injury and multisystem organ failure. Intratracheal administration of adenovirus expressing either human or viral IL-10 prior to zymosan administration significantly improved survival at a dose of 10(7) particles (P<0.01), whereas the same recombinant vectors were ineffective at 10(8) particles and increased mortality at 10(9) particles. Improved survival after administration of 10(7) particles of adenovirus expressing viral or human IL-10 was associated with local tissue expression of IL-10 (100-300 pg/g wet wt). In contrast, mortality after administration of 10(9) particles was associated with markedly elevated IL-10 expression, both in the lung (10000-70000 pg/g wet wt) and systemically (1000-3000 pg/ml plasma), with evidence of an exaggerated systemic inflammatory response (plasma IL-6 and TNFalpha). Targeted gene expression of IL-10 can be used to treat acute inflammatory processes, but increased doses resulting in its systemic release are not associated with improvements in outcome, and may actually exacerbate acute inflammatory processes.
Assuntos
Adenoviridae/genética , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Imunoterapia Ativa/métodos , Interleucina-10/genética , Insuficiência de Múltiplos Órgãos/terapia , Doença Aguda , Animais , Infecções Bacterianas/imunologia , Relação Dose-Resposta Imunológica , Expressão Gênica , Marcação de Genes , Humanos , Interleucina-10/imunologia , Interleucina-6/sangue , Pulmão/imunologia , Pneumopatias/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Insuficiência de Múltiplos Órgãos/imunologia , Insuficiência de Múltiplos Órgãos/mortalidade , Polissacarídeos Bacterianos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Taxa de Sobrevida , Transdução Genética/métodos , Fator de Necrose Tumoral alfa/análise , ZimosanRESUMO
Adenovirus (Ad) gene therapy has been proposed as a drug-delivery system for the targeted administration of protein-based therapies, including growth factors and biological response modifiers. However, inflammation associated with Ad transduction has raised concern about its safety and efficacy in acute inflammatory diseases. In the present report, intratracheal and i.v. administration of a first-generation adenoviral recombinant (E1,E3 deleted) either containing an empty cassette or expressing the anti-inflammatory cytokines viral or human IL-10 (IL-10) was administered to mice subjected to zymosan-induced multisystem organ failure or to acute necrotizing pancreatitis. Pretreatment of mice with the intratracheal instillation of Ad expressing human IL-10 or viral IL-10 reduced weight loss, attenuated the proinflammatory cytokine response, and reduced mortality in the zymosan-induced model, whereas pretreatment with a control adenoviral recombinant did not significantly exacerbate the response. Pretreatment of mice with pancreatitis using adenoviral vectors expressing IL-10 significantly reduced the degree of pancreatic and liver injury and liver inflammation when administered systemically, but not intratracheally. We conclude that adenoviral vectors can be administered prophylactically in acute inflammatory syndromes, and expression of the anti-inflammatory protein IL-10 can be used to suppress the underlying inflammatory process.